Efficacy and safety of tranexamic acid on blood loss and seizures in patients undergoing meningioma resection: A systematic review and meta-analysis

Introduction It is unclear how tranexamic acid (TXA) affects blood loss and seizures in meningioma resections. We performed a systematic review and meta-analysis and tried to evaluate the effectiveness and safety of TXA use for patients undergoing meningioma resections. Methods Regards to this systematic review and meta-analysis (registered with CRD42023416693), we searched PubMed, Embase (Ovid), EBSCO, and Cochrane central library up to and including Oct 2023. Patients undergoing meningioma resections treated with TXA and placebo or no treatment were eligible for this study. This would allow delineation of the impact of TXA on blood loss, postoperative seizure, and other complication incidences. Results Four prospective cohort studies with 781 patients (390 patients in the TXA group and 391 patients in the control group) were conducted via a systematic review and meta-analysis. The results suggested that the application of TXA for patients undergoing meningioma resections reduced mean blood loss of 252 mL with 95% confidence interval (CI) -469.26 to -34.67 (P = 0.02) and I2 of 94% but did not increase postoperative seizure (risk ratio: 1.08; 95%CI: 0.54 to 2.15; P = 0.84) and other complication rates. Conclusions This systematic review and meta-analysis suggests that the administration of TXA could reduce blood loss in patients undergoing intracerebral meningioma resection. Registry information The systematic review protocol has been registered at PROSPERO (Registration No. CRD42023416693) on April 23, 2023.


Introduction
Meningiomas are one of the most common intracranial tumors and comprise approximately 36% of all intracranial neoplasms [1].Although most meningiomas are benign [2], surgical removal is often accompanied by significant blood loss [3].Excessive intraoperative blood loss may cause severe hemodynamic instability followed by cell salvage, large amounts of crystalloids, colloids, and allogeneic blood transfusion [4,5].
Therefore, we performed a systematic review and meta-analysis, and tried to explore the potential evidence for the TXA's efficacy and safety in intracranial meningioma surgery.

Methods
The systematic review protocol has been registered at PROSPERO (Registration No. CRD42023416693) on April 23, 2023.The systematic review and meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [18].

Selection criteria
We incorporated trials that exhibited the following characteristics: (1) trial types: clinical randomized controlled trials/original papers, (2) population: patients undergoing meningioma resection, (3) intervention: at any dose of intravenous TXA, (4) control: placebo or without TXA administration, and (5) outcomes: the primary outcome was intraoperative blood loss, and transfusion requirements, postoperative seizure, and other complication rates are included as the secondary outcomes.

Search strategy
To carry out a systematic review and meta-analysis about the administration of TXA in intracranial meningioma surgery, we searched PubMed, Embase (Ovid), EBSCO, and Cochrane central library up to and including Oct 15, 2023.Randomized controlled trials in the English language comparing TXA with placebo or no treatment in patients undergoing meningioma resection were eligible for this study.The keywords were employed to search PubMed with following mode: ((tranexamic acid) OR (TXA) OR (Tranexamic acid)) AND (meningioma) AND ((randomized controlled trial) OR (randomized)).The same search strategy for PubMed was used to retrieve another two databases [19].

Data extraction
Articles identified by searching using the search terms were combined, and duplicates were removed.After the removal of duplicates, two independent reviewers (M L and S L) screened titles, abstracts, and full-text articles for eligibility using pre-defined criteria.Any discrepancies or disagreements among reviewers were resolved by discussion.If disagreements occur clarification would be sought from the senior authors (YM P).This was illustrated using a PRISMA flow chart.Two authors (M L and S L) collected the study characteristics from each selected study, including publication time, the population, number of patients, the dose of TXA administered, intraoperative blood loss in mL, transfusion requirements, postoperative seizure within hospitalization, postoperative complications and information to assess the risk of bias in the studies.

Quality assessments
M L and S L analyzed independently the risk of systematic errors (bias) of the trials incorporated in the meta-analysis based on the Cochrane Handbook, version 6.1.The Cochrane risk of bias tools were used to assess all the studies included.For randomized studies, the Risk of Bias version 2 (RoB 2) tool (version 22 August 2019) was used.
The assessment of bias risk was based on the following domains (1) randomization or nonrandomization; (2) deviation from intended intervention; (3) missing outcome data; (4) measurement of the outcome; (5) selection of reported result.

Outcomes
The primary outcome was intraoperative blood loss.The secondary outcomes were transfusion requirements and complication rate, including postoperative seizure, hematoma, and thrombosis events.

Statistical analysis
Statistical analyses were conducted with Review Manager Software 5 (Review Manager [Rev-Man] Version 5.4 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020).For the continuous data, such as blood loss, the mean ± standard deviation was employed to calculate the weighted mean difference (WMD) and 95% confidence interval (CI) were applied.Statistical heterogeneity among the trials was tested by inspection of forest plot and calculation of I 2 statistics.A p-value < 0.1 and an I 2 value > 50% were considered to be suggestive of statistical heterogeneity.We utilized a random-effect model regardless of the I 2 caused by the meta-analysis application.All tests were two-tailed, and the result was presented as statistical significance when the P-value was less than 0.05.

Literature search
Totally, we screened 326 abstracts, did a full-text review on 31 of them, and selected four trials enrolling 390 participants who received TXA usage and 391 participants with a placebo for the meta-analysis in this study ( Fig 1).

Description of selected studies
Table 1.summarizes the characteristics of selected trials.In three studies [3,20,21], TXA was administered through a loading dose of 20 mg/kg and a continuous infusion at 1 mg/kg/h until the completion of the surgery.Shu Li 2023 [19] involved a single dose of TXA at 20 mg/ kg.

Risk of bias in individual trials
Overall, one trial [19] was regarded as low risk of bias.Four trials [3,[19][20][21] were deemed at low risk of bias for randomized process, deviation from intended interventions.One trial [19] was judged at low risk of bias for missing outcome data and selection of reported result.Supplementary material attached exhibits the risk of bias of the selected trials (S1 and S2 Figs).

Outcomes
Blood loss and blood transfusion requirements.A total of 781 patients from four studies [3,[19][20][21] were eligible for the primary outcome.Compared with the control group, the administration of TXA distinctly reduced intraoperative blood loss of 252 mL with 95% CI -469.26 to -34.67 (P = 0.02; Fig 2A).A pooled WMD for all patients was completed, and the data showed significant heterogeneity (I 2 = 94%; Fig 2A).
Incidence of postoperative seizure and incidence of other postoperative complications.A total of 751 patients were included in three studies [3,19,21] relevant to this outcome.The use of TXA did not increase the risk of postoperative seizure compared with the control group (risk ratio: 1.08; 95%CI: 0.54 to 2.15; I 2 = 0%; P = 0.84; Fig 2B).Only one study [19] mentioned the prophylactic administration of antiepileptic drugs postoperatively, while the other studies [3,20,21] did not specify this.

Discussion
The systematic review and meta-analysis in our study showed that intravenous TXA administration could reduce blood loss in patients undergoing meningioma resections without increasing the risk of postoperative seizure or other postoperative complications.Despite TXA having been reported to reduce blood loss and transfusion requirements in a variety of surgical settings, the use of TXA in patients undergoing neurosurgery is limited.A previous meta-analysis [22] conducted by Jeremiah et al. indicated administration of TXA reduced total blood loss of standardized mean difference of -1.40 (95%CI: -2.49 to -0.31; P = 0.01) and blood transfusion requirements risk ratio 0.58 (95%CI: 0.34 to 0.99; P = 0.48).Our results also showed that TXA could reduce a mean volume of 252 mL of intraoperative blood loss (95%CI: -469.26 to -34.67; P = 0.02; Fig 2A) with high heterogeneity (I 2 = 94%).We explored the following possible explanations for notable heterogeneity: first, differences exist in the populations enrolled across the four trials.Two trials [3,20] enrolled patients with meningioma diameter � 4 cm, while others [19,21] had no criteria on tumor size.In general, the larger the tumor diameter, the more blood loss occurred during tumor resection.Furthermore, blood loss is influenced by tumor location, its relationship to venous sinuses, vascular supply, and whether there was perioperative embolization as well.And the estimation of blood loss by the anesthesiologist might be subject to a margin of error and differ in included trials.For blood transfusion requirements, transfusion trigger for RBC were also various in four trials.Three trials were hemoglobin concentration <8 g/dL [3,19,21], while another was hematocrit �27% [20].The elements mentioned above might result in heterogeneity in transfusion requirements.
With regard to TXA dosing, official recommendations or guidelines are currently lacking.A prospective interventional dose-dependent study discovered that intraoperative low-dose TXA (10 mg/kg followed by 1 mg/kg/hour over 12 h) infusion effectively reduced intraoperative blood loss by 36% (365 mL vs. 552 mL; P = 0.042) in cardiac surgery [23].A meta-analysis on the impact of a single preoperative dose of TXA found that administering a single dose of 10-20mg/kg TXA reduced 148 mL of blood loss and lower transfusion rates by 74% without a concomitant increase in the occurrence of venous thromboembolic events in orthopedic, obstetric, and gynecologic surgeries [24].In a randomized controlled trial with 100 patients undergoing elective craniotomy for tumor excision, lower intraoperative blood loss was demonstrated (817 mL vs. 1084 mL; P = 0.012) in the TXA group with a bolus dose of 10-25 mg/kg followed by 1-10mg/kg/hour, while no patient in the study suffered from a complication related to the administration of TXA [25].In our meta-analysis, the TXA dose of three trials [3,20,21] ranged from 4 g to 7 g, and Shu Li 2023 was approximately 100-150 mg [19].None of the three studies [3,20,21] increased the incidence of TXA-associated perioperative complications.Moreover, our meta-analysis suggested that TXA reduced blood loss without increasing the risk of perioperative complications, which were in accordance with the findings of the individual study included in the meta-analysis.The meta-analysis [22] mentioned above also suggested that TXA did not result in a significant rise in the occurrence of postoperative seizure and hemostatic events.

Limitations
Some limitations of our meta-analysis need to be considered.Firstly, the crucial data in a part of selected studies were missed, for example, a randomized controlled trial performed by Ravi et al did not provide the volume of transfused RBC and postoperative seizure [20].In addition, we collected studies through systematically searching selected databases, nevertheless the potential for publication bias persists.Secondly, there was heterogeneity when comparing the blood loss between the TXA and the control group.The multiple analyses in the studies chosen in the meta also led to the high value of I 2 .The variables that may cause the heterogeneity include the difference in the dosing and timing of TXA administration, tumor size, tumor location, blood transfusion protocols, surgical techniques, approach and methods, as well as different strategies for measuring outcomes.Thirdly, only four studies were selected, and the sample size of the individual studies was limited.Additionally, there was no available data about thrombosis events for TXA administration in an anticoagulant state.Last, though two of the four studies excluded patients with preoperative seizures, only one study reported the use of anticonvulsive therapy, leading to an inconclusive effect of TXA on postoperative seizure.

Conclusions
This systematic review and meta-analysis suggests that the administration of TXA could reduce blood loss in patients undergoing intracerebral meningioma resection.However, due to the heterogeneity of studies, the impact of TXA on the risk of seizure or other postoperative complications remains inconclusive.Large multi-center clinical trials are needed to fully confirm the effect of TXA administration in saving blood loss and postoperative seizures in the neurosurgical population.